tbuckley/cabot-search huggingface dataset:
Abstract 5226: The PI3K inhibitor Paxalisib combines synergistically with the pan-Raf inhibitor TAK580 (DAY 101) to extend survival in orthotopic xenograft models of atypical teratoid/rhabdoid tumors
Authors: Kristen Malebranche, Tyler Findlay, Charles Eberhart, Eric Raabe, Jeffrey Rubens
Journal: Cancer Research (2022)

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive pediatric brain tumors and the most common malignant brain tumors of infancy. The four-year event-free survival rate is only 37%. For patients with relapsed AT/RT, there are limited treatment options, but novel precision therapies may help improve survival for patients with this deadly disease. We have previously identified strong activation of the PI3K-AKT-mTOR (mTOR) signaling pathways in AT/RT. Paxalisib is a highly brain-penetrant PI3K inhibitor acting upstream of mTOR. We find that Paxalisib slows tumor growth in orthotopic xenograft models of AT/RT and extends median survival from 40 to 54 days (p=0.001, log-rank test). RNASeq after mTOR pathway inhibition identifies reflexive activation of the MAPK pathway as a possible mechanism of therapy resistance (KEGG pathway analysis). TAK580 (DAY 101) is a highly brain penetrant, pan-RAF kinase inhibitor, currently in clinical trials in pediatric low grade gliomas (NCT03429803, NCT04775485). Paxalisib combines synergistically with TAK580 to reduce AT/RT growth and viability (Bliss synergy score 24.22). A pilot study suggests combination therapy is well tolerated in mice bearing AT/RT orthotopic xenografts and slows tumor growth compared to Paxalisib alone and vehicle controls. This novel combination of precision therapies can translate into a clinical trial aimed at improving survival in this deadly disease. Citation Format: Kristen Malebranche, Tyler Findlay, Charles Eberhart, Eric Raabe, Jeffrey Rubens. The PI3K inhibitor Paxalisib combines synergistically with the pan-Raf inhibitor TAK580 (DAY 101) to extend survival in orthotopic xenograft models of atypical teratoid/rhabdoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5226.
Abstract 1208: Denoising spatial expression profiling data based on in situ position and image information
Authors: Yunguan Wang, Bing Song, Shidan Wang, Mengyi Chen, Yang Xie, Guanghua Xiao, Li Wang, Tao Wang
Journal: Cancer Research (2022)

Abstract Spatial expression profiling (SEP) technologies provide gene expression close to or even superior to single-cell resolution while retaining the physical locations of sequencing and often also providing matched pathology images. However, the expression data captured by SEP technologies suffer from high noise levels, including but not limited to dropouts as in regular single-cell RNA-sequencing (scRNA-seq). The extra experimental steps for preserving the spatial locations of sequencing could result in even more severe noises, compared to regular scRNA-seq. Fortunately, such noises could be largely reduced by leveraging information from the physical locations of sequencing and the tissue and cellular organization reflected by corresponding pathology images. In this work, we demonstrated the extensive levels of noise in SEP data. We developed a mathematical model, named Sprod, to reduce such noises based on latent space and graph learning of matched location and imaging data. We comprehensively validated Sprod and demonstrated its advantages over prior methods for removing dropouts in scRNA-seq data. We further showed that, after adequately de-noising by Sprod, differential expression analyses, pseudotime analyses, and cell-to-cell interaction inferences yield significantly more informative results in various biological application settings. In particular, with Sprod, we discovered 3-4 times more RNA transcripts that were actively transported in mouse hippocampus neurons. We also showed that the tumor cells at the tumor-stroma boundaries demonstrate differential transcriptomic features from the tumor cells in the central regions, caused by their interactions with the stroma/immune cells. Overall, we envision denoising by Sprod to become a key first step to empower SEP technologies for biomedical discoveries and innovations. Citation Format: Yunguan Wang, Bing Song, Shidan Wang, Mengyi Chen, Yang Xie, Guanghua Xiao, Li Wang, Tao Wang. Denoising spatial expression profiling data based on in situ position and image information [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1208.
Efficacy and Safety of Intensive Versus Nonintensive Supplemental Insulin With a Basal-Bolus Insulin Regimen in Hospitalized Patients With Type 2 Diabetes: A Randomized Clinical Study
Authors: Priyathama Vellanki, Saumeth Cardona, Rodolfo J. Galindo, Maria A. Urrutia, Francisco J. Pasquel, Georgia M. Davis, Maya Fayfman, Alexandra Migdal, Limin Peng, Guillermo E. Umpierrez
Journal: Diabetes Care (2022)

Administration of supplemental sliding scale insulin for correction of hyperglycemia in non-intensive care unit (ICU) patients with type 2 diabetes is frequently used with basal-bolus insulin regimens. In this noninferiority randomized controlled trial we tested whether glycemic control is similar with and without aggressive sliding scale insulin treatment before meals and bedtime in patients treated with basal-bolus insulin regimens.Patients with type 2 diabetes with admission blood glucose (BG) 140-400 mg/dL treated with basal-bolus insulin were randomized to intensive (correction for BG >140 mg/dL, n = 108) or to nonintensive (correction for BG >260 mg/dL, n = 107) administration of rapid-acting sliding scale insulin before meals and bedtime. The groups received the same amount of sliding scale insulin for BG >260 mg/dL. Primary outcome was difference in mean daily BG levels between the groups during hospitalization.Mean daily BG in the nonintensive group was noninferior to BG in the intensive group with equivalence margin of 18 mg/dL (intensive 172 ± 38 mg/dL vs. nonintensive 173 ± 43 mg/dL, P = 0.001 for noninferiority). There were no differences in the proportion of target BG readings of 70-180 mg/dL, <70 or <54 mg/dL (hypoglycemia), or >350 mg/dL (severe hyperglycemia) or total, basal, or prandial insulin doses. Significantly fewer subjects received sliding scale insulin in the nonintensive (n = 36 [34%]) compared with the intensive (n = 98 [91%] [P < 0.0001]) group with no differences in sliding scale insulin doses between the groups among those who received sliding scale insulin (intensive 7 ± 4 units/day vs. nonintensive 8 ± 4 units/day, P = 0.34).Among non-ICU patients with type 2 diabetes on optimal basal-bolus insulin regimen with moderate hyperglycemia (BG <260 mg/dL), a less intensive sliding scale insulin treatment did not significantly affect glycemic control.
Abstract 925: A genetically engineered mouse model for carcinogenesis by the human enzyme APOBEC3B
Authors: Cameron C. Durfee, Prokopios P. Argyris, Matthew C. Jarvis, Rena Levin-Klein, Emily K. Law, Reuben S. Harris
Journal: Cancer Research (2022)

Abstract Introduction: Advanced DNA sequencing technologies have revealed a substantial endogenous source of mutations in cancers, the human DNA-mutating enzyme APOBEC3B (A3B). This protein changes DNA cytosines into uracils (C-to-U), which can become “immortalized” in the genome as C-to-T or C-to-G mutations depending on how each uracil lesion is processed. However, mice lack analogous carcinogenic A3 enzymes, which makes a definitive cause-and-effect model of A3-induced carcinogenesis difficult to establish. Results: Using C57BL/6 mice, we have generated a novel genetically engineered mouse model (GEMM) expressing the human protein A3B, where it is driven constitutively from the Rosa26 locus in combination with the strong synthetic CAG promoter. Importantly, tumor-free survival data suggest that CAG A3B mice develop tumors at an increased rate compared to wild-type mice. These CAG A3B mice develop predominantly lymphoid neoplasms including B- and T-cell lymphomas and marked splenomegaly, and less frequently lung and liver cancers. Using immunohistochemical and whole-genome sequencing techniques, we have further characterized the tumors arising in these novel GEMMs. The above analyses thus far have revealed that A3B is actively driving tumor formation, as seen by an enrichment of canonical APOBEC-related mutations in these cancers. Conclusion: Overall, the CAG A3B mice are the first GEMMs demonstrating the potential for A3B to drive tumor formation in vivo, with a predilection towards blood malignancies. They will be an invaluable tool for characterizing A3B-driven mutational processes in an organism and testing novel therapeutic strategies against APOBEC-induced cancer initiation and progression. Citation Format: Cameron C. Durfee, Prokopios P. Argyris, Matthew C. Jarvis, Rena Levin-Klein, Emily K. Law, Reuben S. Harris. A genetically engineered mouse model for carcinogenesis by the human enzyme APOBEC3B [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 925.
Nivolumab Retreatment in Non–Small Cell Lung Cancer Patients Who Responded to Prior Immune Checkpoint Inhibitors and Had ICI-Free Intervals (WJOG9616L)
Authors: Hiroaki Akamatsu, Shunsuke Teraoka, Shinkichi Takamori, Satoru Miura, Hidetoshi Hayashi, Akito Hata, Yukihiro Toi, Yoshimasa Shiraishi, Nobuaki Mamesaya, Yuki Sato, Naoki Furuya, Jun Oyanagi, Yasuhiro Koh, Toshihiro Misumi, Nobuyuki Yamamoto, Kazuhiko Nakagawa
Journal: Clinical Cancer Research (2022)

To explore the efficacy of retreatment with immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) patients who responded to prior ICI and had adequate ICI-free interval.Advanced NSCLC patients who had achieved complete response (CR), partial response (PR), or stable disease for {greater than or equal to}6 months with prior ICI therapy preceding progression were prospectively enrolled. All patients should have had ICI-free interval {greater than or equal to} 60 days before registration. Patients were treated with nivolumab (240 mg/body) every 2 weeks until progression. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival, and safety (Trial Identifier, UMIN000028561).Sixty-one patients were enrolled during October 2017-February 2020, with 59 analyzed for efficacy. Regarding prior ICI, 41 patients had CR or PR. Median treatment on ICI and median ICI-free intervals were 8.1 months and 9.2 months, respectively. Twenty patients experienced immune-related adverse events (irAEs) that required discontinuation of prior ICI. Nivolumab retreatment demonstrated ORR of 8.5% (95% confidence interval [CI]: 2.8-18.7%) and median PFS of 2.6 months (95% CI: 1.6-2.8 months) while five responders had 11.1 months of median PFS. In the multivariate analysis, ICI-free interval was the only predictive factor of PFS (hazard ratio: 2.02, p = 0.02), while prior efficacy or history of irAE was not. Common adverse events were skin disorders (23%), malaise (20%), and hypoalbuminemia (15%).Even in patients who initially responded to prior ICI and had ICI-free interval, once resistance occurred, retreatment with nivolumab had limited efficacy.
Abstract 247: Targeting Notch4 with a novel neutralizing antibody inhibits tumor growth and alters immune cell populations within the tumor microenvironment
Authors: Jason Eng, L.A. Naiche, Bhairavi Swaminathan, Yu Kato, Krishna Thakkar, Rahul Vadakath, James Herts, Rajyasree Emmadi, Junji Matsui, Jan Kitajewski
Journal: Cancer Research (2022)

Abstract Endothelial Notch signaling is critical for tumor angiogenesis and growth. Inhibition of Notch1 or its ligand, Dll4, can induce tumor vessel hypersprouting, which interferes with perfusion and reduces tumor development. Unfortunately, blocking Notch1 in endothelial cells of normal tissue can lead to tissue hypoxia and vascular neoplasms. Notch4, another member of the Notch family, is upregulated and increased in the endothelium of certain tumor types compared to normal vasculature. Reducing Notch4, unlike Notch1, causes reduction in developmental and tumor angiogenesis. Using a newly developed anti-Notch4 antibody, E7011, we assessed the effects on Notch4 inhibition on developmental retinal angiogenesis. E7011 treatment did not alter capillary density within the vascular plexus or endothelial tip cell number, but did decrease radial outgrowth and vein diameter, supporting the hypothesis that Notch4 functions as a pro-angiogenic signal. These findings suggest that the targeting of Notch4 could interfere with tumor angiogenesis and offer a novel therapeutic avenue. To establish the role of Notch4 within the tumor microenvironment, we analyzed its expression in both human and murine tumor samples. Immunofluorescent staining revealed a range of Notch4 expression in both tumor cells and endothelium in human triple negative breast cancers. Several murine syngeneic tumors examined expressed Notch4 primarily in the endothelium with only rare tumor expression. We treated orthotopically implanted Py8119 murine breast carcinomas and B16F10 melanomas with E7011, which significantly reduced tumor size compared to IgG treated controls, indicating that suppression of Notch4 is anti-tumorigenic. To determine mechanistically how E7011 delays tumor growth, we performed single cell RNA sequencing on E7011 and control treated Py8119 tumors. Surprisingly, we found that while Notch4 transcripts were present only in endothelial cells, E7011 administration dramatically altered macrophage and monocyte populations within the tumor. Taken together, these findings indicate that inhibition of tumor endothelial Notch4 by E7011 can regulate the presence of immune cells within the tumor microenvironment and improve tumor control. Citation Format: Jason Eng, L.A. Naiche, Bhairavi Swaminathan, Yu Kato, Krishna Thakkar, Rahul Vadakath, James Herts, Rajyasree Emmadi, Junji Matsui, Jan Kitajewski. Targeting Notch4 with a novel neutralizing antibody inhibits tumor growth and alters immune cell populations within the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 247.
Abstract 824: Loss of Parkin's inactivation by autoubiquitination induces prostate cancer tumorigenesis
Authors: SeungBaek Lee
Journal: Cancer Research (2022)

Abstract Mutations in the E3 ubiquitin ligase Parkin have been linked to familial Parkinson’s disease as well as various human cancers. Although the activation of Parkin's E3 ligase is well characterized, the mechanism that tunes down tumorigenesis by phosphorylation-mediated auto-ubiquitination is largely unknown. Here we found that Parkin S378 is phosphorylated in mitosis while Parkin S131 is phosphorylated in late G1-S. Parkin protein levels were significantly lower in interphase compared to mitosis. Also, we checked that parkin itself degraded the protein by autoubiquitination in the cells overexpressing Parkin S131. Parkin S131D mutant significantly increased the rate of tumorigenesis compared to the control in in vitro and mouse models. Furthermore, Parkin S131 mutation was found in several patients with prostate cancer. These results suggest that the inactivation of Parkin by auto-ubiquitination impairs its ubiquitination activity and abolishes its tumor-suppressive effect in prostate cancer. Citation Format: SeungBaek Lee. Loss of Parkin's inactivation by autoubiquitination induces prostate cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 824.
Clinical profile and outcome of solid pseudopapillary neoplasm of the pancreas: A retrospective study on 28 patients
Authors: Arkadeep Dhali, Sukanta Ray, Somak Das, Tuhin Subhra Mandal, Sujan Khamrui, Arunesh Gupta, Zuber Ansari, Ranajoy Ghosh, Gopal Krishna Dhali
Journal: International Journal of Surgery (2022)
Abstract 5620: CD34+humanized huHSC-NCG mice engrafted with hematological malignancies models for preclinical study of anti-human CD19 therapeutic antibodies
Authors: Weiwei Yu, Cunxiang Ju, Hongyan Sun, Mingkun Zhang, Honghong Bao, Shuai Li, Chao Ju, Jing Zhao, Xiang Gao
Journal: Cancer Research (2022)

Abstract CD19, has become a vital immune and cellular therapeutic target to treat B-cell malignancies, as anti CD19 antibodies has produced remarkable clinical outcomes. Due to the lack of functional murine T cells, as well as B and NK cells, NCG mice engrafted with CDX or PDX models are well suited for evaluating CAR-T anti-tumor efficacy, but do not meet the needs of evaluating in vivo anti-tumor efficacy of anti-human CD19 bispecific or tri-specific antibodies that require functional human T cells.huHSC-NCG mice were established by the engraftment of CD34+ hematopoietic stem cells (HSC) into irradiated NCG mice. Among multi-lineages of human immune cells, the level of reconstituted human CD3+ T cells gradually increased in huHSC-NCG mice from 10 weeks after engraftment for long-term efficacy evaluation study. Both CD8+ cytotoxic and CD4+ helper T lymophocytes were detected by FACS in blood circulation. In this study, we established mice engrafted with Raji-Luciferase lymphoma and orthotopically engrafted with Nalm6-Luciferase leukemia cells. Both Blinatumomab and tri-specific antibodies displayed a pharmacological effect by reducing the proportion and total counts of B cells in circulation, showed significant tumor growth inhibition and prolonged the survival of xenograft huHSC-NCG mice. Taken together, huHSC-NCG mice is an ideal mouse model for preclinical study of bi-specific or tri-specific T cell engager therapeutic antibodies. Citation Format: Weiwei Yu, Cunxiang Ju, Hongyan Sun, Mingkun Zhang, Honghong Bao, Shuai Li, Chao Ju, Jing Zhao, Xiang Gao. CD34+humanized huHSC-NCG mice engrafted with hematological malignancies models for preclinical study of anti-human CD19 therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5620.
Abstract 2528: PDLIM2 expression in triple negative breast cancer stromal macrophages
Authors: Orla T. Cox, Stephanie Ward, Emilie Tresse, Rosemary O'Connor
Journal: Cancer Research (2022)

Abstract PDLIM2 is a PDZ-LIM domain protein expressed in hematopoietic and epithelial cells that regulates the stability of transcription factors including NFΚB, STATs and beta catenin. PDLIM2 function is associated with tumour suppression and also with the acquisition of a metastatic or epithelial mesenchymal transition (EMT) phenotype. We recently showed that PDLIM2 is more highly expressed in Triple Negative Breast Cancer (TNBC) tumours than in other breast cancer types or normal breast tissue, and that this is associated with active beta catenin in TNBC (1). Interestingly, in PDLIM2-positive TNBC tumours, PDLIM2 was also present in the tumour-associated stroma. However, whether stromal PDLIM2 expression contributes to TNBC cancer progression is unknown. To investigate this further we assessed the phenotype of PDLIM2-expressing stromal cells and determined that they most strongly represented a M2-like macrophage population. We then investigated the requirement for PDLIM2 in polarization towards either the M1 and M2-like macrophage phenotype using cultured bone marrow-derived macrophages from PDLIM2 knockout mice compared with wild type. This demonstrated that PDLIM2 is required for full adoption of IL-4-induced M2 macrophage polarization and function, including cell adhesion and migration. M1 polarization was less dependent on PDLIM2, although potential for activation of STATs and NFKB was similar in both macrophage populations.We conclude that high expression of PDLIM2 in TNBC influences the tumour microenvironment through the presence of an M2 macrophage population. Reference: (1) Cox, O. T., Edmunds, S. J., Simon-Keller, K., Li, B., Moran, B., Buckley, N. E., Bustamante-Garrido, M., Healy, N., O'flanagan, C. H., Gallagher, W. M., Kennedy, R. D., Bernards, R., Caldas, C., Chin, S. F., Marx, A. &amp; O'Connor, R. 2019. Pdlim2 Is A Marker Of Adhesion And Beta-Catenin Activity In Triple-Negative Breast Cancer. Cancer Res, 79, 2619-2633. Citation Format: Orla T. Cox, Stephanie Ward, Emilie Tresse, Rosemary O'Connor. PDLIM2 expression in triple negative breast cancer stromal macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2528.
Abstract 5251: GRIN2A mutations as potential positive predictor for response of immune checkpoint inhibitors in melanoma
Authors: Ling Ye, Dandan Fan, Yaoxu Chen, Mengli Huang
Journal: Cancer Research (2022)

Abstract Background: Melanoma is a serious skin cancer. Immune checkpoint inhibitors (ICIs) including atezolizumab, pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. Studies have shown that Tumor Mutation Burden (TMB) was significantly (p &amp;lt; 0.001) associated with mutations in genes like GRIN2A in Non-Small Cell Lung Cancer (NSCLC), which means that the mutation of GRIN2A gene may be related to the efficacy of immunotherapy in patients with NSCLC, but the association between GRIN2A mutation and TMB or survival in melanoma is unknown. Methods: The association between GRIN2A mutation with TMB and survival data was analyzed in melanoma patients from the public immunotherapy-treated cohort called Miao2018.Pancancer.249.WES, which worked as training cohort while the validation cohort was retrieved from Melanoma.Allen2015.WES.110. Wilcoxon test was used for the comparison of TMB and Tumor Neoantigen Burden (TNB). Progress Free Survival (PFS):Overall survival (OS) analyses were conducted in the public cohort using Kaplan-Meier curves and log-rank tests. Statistical significance was set at p=0.05. Results: In the training cohort, 33.8% (51/151) melanoma patients harbored GRIN2A mutation. GRIN2A mutation is associated with higher TMB (p&amp;lt;0.001) and higher TNB (p&amp;lt;0.001). Survival analysis demonstrated that GRIN2A mutation resulted in significantly longer PFS (5.6 vs 3.3months; HR, 0.58; p=0.027) and longer OS (22.5 vs 12.8 months; HR, 0.61; p=0.039) in melanoma patients treated with ICIs. While validation cohort1 showed that 22.7% (25/110) melanoma patients harbored GRIN2A mutation and GRIN2A mutation resulted in an increasing trend on TMB with strongly significant difference (p&amp;lt;0.001) and significantly longer OS (22.5 vs 8.3months; HR, 0.53; p=0.025). Conclusions: This study shows that GRIN2A mutation is correlated with higher TMB and TNB in melanoma and serve as a predictive biomarker of ICI benefit in melanoma. Citation Format: Ling Ye, Dandan Fan, Yaoxu Chen, Mengli Huang. GRIN2A mutations as potential positive predictor for response of immune checkpoint inhibitors in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5251.